Phosphonates, aldehyde reaction

Another method for the preparation of hydroxyalkanephosphonic acids is the conversion of aldehydes with dialkyl phosphites in the presence of triethylamine or sodium methylate leading directly to the corresponding a-hydroxyalkane-phosphonates. This reaction is reversible, leading to the starting materials aldehyde and diethyl phosphite again [143,146]. 

A tandem enzymatic aldol-intramolecular Homer-Wadsworth-Emmons reaction has been used in the synthesis of a cyclitol.310 The key steps are illustrated in Scheme 8.33. The phosphonate aldehyde was condensed with dihydroxyacetone phosphate (DHAP) in water with FDP aldolase to give the aldol adduct, which cyclizes with an intramolecular Horner-Wadsworth-Emmons reaction to give the cyclo-pentene product. The one-pot reaction takes place in aqueous solution at slightly acidic (pH 6.1-6.8) conditions. The aqueous Wittig-type reaction has also been investigated in DNA-templated synthesis.311... 

Phosphonate Aldehyde/ketone Reaction conditions % yield of alkene... 

Reaction of dienoaldehyde with the stabilized Wittig reagent(s) provided a triene 88, which upon high-pressure Diels-Alder cyclization furnished bicyclo[4.3.0]nonene [78]. Alternatively the aldehyde S7-E was converted into the methyl ester 89, which reacted with the dimethyl methylphosphonate anion affording the phosphonate 90. Reaction of the latter with aldehydes under mild PTC conditions yielded a (regioisomeric to the previous one) triene 91, which cyclized spontaneously to bicyclo[4.4.0]decene (O Scheme 37) [79]. 

In a similar way, pyridine phosphonium salts and phosphonates can be prepared by reaction of trivalent phosphorus compounds with the more accessible iV-trifluoromethanesulfonyl-pyridinium salts, when tri-fluoromethanesulfone is the leaving group from nitrogen (as sulfinate anion) attack is normally at C-4, as illustrated below. The A -trifluoromethanesulfonyl-pyridinium salts also react with ketones or with electron-rich aromatic compounds to give 1,4-dihydropyridine adducts. Subsequent treatment with potassium t-butoxide brings about elimination of trifluoromethanesulfinic acid, and thus aromatisation. It is also possible to utilise phosphonates in reaction with aldehydes, leading finally to 4-substimted pyridines. ... 

A modified Horner-Wadsworth-Emmons reagent with high Z stereoselectivity using trifluoroethyl phosphonates in reaction with saturated, unsaturated or aromatic aldehydes. 

A Wadsworth-Emmons reaction of the phosphonate (250) with the aldehyde (251) has been used as a key step in a total synthesis of analogues (252) and (253) of topostin B-1, an inhibitor of mammalian DNA topoisomerase The enzyme-catalysed aldol condensation between the phosphonate aldehyde (254) and dihydroxyacetone phosphate is followed by spontaneous intramolecular olefination of the product to give the cyclitol (256) in spite of the reaction being below pH 7 at all times.Attempts at a similar reaction of the homologue (255) were unsuccessful probably because (255) is a poor substrate for the aldolase. 

The use of oxirane together with Na2HP03 to prepare (2-hydroxyethyl)phosphonic acid as its disodium salt is of historical interest. Other poorly exploited, yet interesting and potentially valuable, reactions include the combination of a trialkyl phosphite and dialkyl chlorophosphate with an oxirane to yield O-phosphorylated derivatives of (2-hydrox-yalkyl)phosphonic diesters (reaction 10)" and, following the initial reaction of an a,j8-unsaturated ketone with a phosphorus(III) triester to give the cyclic phosphorane 272, the subsequent further reaction of the latter with an aldehyde followed by hydrolysis (reaction 11)" Dialkyl acetyl phosphites are reported to react with oxirane through anionic intermediate species with the formation, albeit in low yields, of dialkyl (2-acetyloxyethyl)phos-phonates hydrolysable with concentrated HCl, to give (2-hydroxyethyl)phosphonic acid ... 

One further reaction may be noted, although not extensively explored. In the initial report, aldehydes or ketones react with dichlorothiophosphites, when the products are ethers of (1 -mercaptoalkyl)phosphonic dichlorides (reaction 18) reactions which involved benzaldehyde or acetone proceeded with only moderate yields In a second report, use is made of combinations of carbonyl reactant, thiol and phosphorus(III) chloride, and it is conceivable that the actual reactants are essentially those mentioned in the first report ... 

The preparation of potential polyene macrolide mimics by cyclodimerization of symmetrical segments was reported by Floyd and Fritz [148] in 1982 using a phosphonate-aldehyde coupling as a key ring closure reaction. Diphosphonate 245 was obtained from diphosphonate 243 by reaction with aldehyde 244, deprotection to a triene diol, and esterification with dimethyl phosphonoacetyl chloride (Scheme 34). Condensation with dialdehyde 246 provided the desired macrocycle 248. A closer mimic bearing a 1,3-polyol chain 249 was also prepared by reacting the all-syn triacetate 247 obtained in a three-step process from endoperoxide 250 [149] with diphosphonate 245. 

Adducts from various quaternary salts have been isolated, in reactions with aldehydes, a-ketoaldehydes, dialkylacylphosphonates and dialkyl-phosphonates, isocyanates, isothiocyanates, and so forth (Scheme 15) (36). The ylid (11) resulting from removal of a Cj proton from 3.4-dimethyl-S-p-hydroxyethylthiazolium iodide by NEtj in DMF gives with phenylisothiocyanate the stable dipolar adduct (12) that has been identified by its NMR spectrum and reactional product, such as acid addition and thiazolidine obtention via NaBH4 reduction (Scheme 16) (35). It must be mentioned that the adduct issued from di-p-tolylcarbodiimide is separated in its halohydrogenated form. An alkaline treatment occasions an easy ring expansion into a 1,4-thiazine derivative (Scheme 17) (35). 

The reaction has been extended to include carbanions generated from phosphonates. This is often referred to as the Horner-Wittig or Homer-Emmons reaction. The Horner-Emmons reaction has a number of advantages over the conventional Wittig reaction. It occurs with a wider variety of aldehydes and ketones under relatively mild conditions as a result of the higher nucleophilicity of the phosphonate carbanions. The separation of the olefinic product is easier due to the aqueous solubility of the phosphate by-product, and the phosphonates are readily available from the Arbusov reaction. Furthermore, although the reaction itself is not stereospecific, the majority favor the formation of the trans olefin and many produce the trans isomer as the sole product. 

Aldehyde 170 is to serve as the electrophile in an intermolecular Homer-Wadsworth-Emmons (HWE) reaction70 with enantiomeri-cally pure phosphonate 169. Compounds 169 and 170 can in fact be joined efficiently under the mild reaction conditions shown in Scheme 50 to give a,/ -unsaturated imide 206 (96 % yield). The use... 

Alkylation of enamines Addition of amines to triple-bond compounds Addition of amines to aldehydes or ketones Reaction between Grignard reagents and formamides Reaction of phosphonates with aldehydes or ketones... 

The reaction of the aldehyde 174, prepared from D-glucose diethyl dithio-acetal by way of compounds 172 and 173, with lithium dimethyl methyl-phosphonate gave the adduct 175. Conversion of 175 into compound 176, followed by oxidation with dimethyl sulfoxide-oxalyl chloride, provided diketone 177. Cyclization of 177 with ethyldiisopropylamine gave the enone 178, which furnished compounds 179 and 180 on sodium borohydride reduction. 0-Desilylation, catalytic hydrogenation, 0-debenzyIation, and acetylation converted 179 into the pentaacetate 93 and 5a-carba-a-L-ido-pyranose pentaacetate (181). 

The synthetic P-o-glucopyranoside 30 was converted to the cyanoglucoside rho-diocyanoside A (38a), which was isolated from the underground part of Rhodiola quadrifida (Pall.) Fisch. et Mey. (Crassulaceae) and found to show antiallergic activity in a passive cutaneous anaphylaxis test in rat. Acetylation of 30 gave an acetate (98% yield) which was subjected to ozonolysis to afford the aldehyde 39. The Horner-Emmons reaction of 39 using diethyl (l-cyanoethyl)phosphonate furnished (Z)-40a (32% yield from 30) and ( )-40b (10% yield from 30). The physical... 

---